Abstract

Experience governs neurogenesis from radial-glial neural stem cells (RGLs) in the adult hippocampus to support memory. Transcription factors in RGLs integrate physiological signals to dictate self-renewal division mode. Whereas asymmetric RGL divisions drive neurogenesis during favorable conditions, symmetric divisions prevent premature neurogenesis while amplifying RGLs to anticipate future neurogenic demands. The identities of transcription factors regulating RGL symmetric self-renewal, unlike those that regulate RGL asymmetric self-renewal, are not known. Here, we show in mice that the transcription factor Kruppel-like factor 9 (Klf9) is elevated in quiescent RGLs and inducible, deletion of Klf9 promotes RGL activation state. Clonal analysis and longitudinal intravital 2-photon imaging directly demonstrate that Klf9 functions as a brake on RGL symmetric self-renewal. In vivo translational profiling of RGLs lacking Klf9 generated a molecular blueprint for RGL symmetric self-renewal that was characterized by upregulation of genetic programs underlying Notch and mitogen signaling, cell-cycle, fatty acid oxidation and lipogenesis. Together, these observations identify Klf9 as a transcriptional regulator of neural stem cell expansion in the adult hippocampus.

Data availability

Sequencing data have been deposited in GEO under accession code GSE164889.

The following data sets were generated

Article and author information

Author details

  1. Nannan Guo

    Center for Regenerative Medicine, Massachusetts General Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Kelsey D McDermott

    Dominick Purpura Department of Neuroscience, Albert Einstein College of Medicine, New York City, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Yu-Tzu Shih

    Center for Regenerative Medicine, Massachusetts General Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Haley Zanga

    Center for Regenerative Medicine, Massachusetts General Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Debolina Ghosh

    Center for Regenerative Medicine, Massachusetts General Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Charlotte Herber

    Center for Regenerative Medicine, Massachusetts General Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. William R Meara

    Center for Regenerative Medicine, Massachusetts General Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. James H Coleman

    Center for Regenerative Medicine, Massachusetts General Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Alexia Zagouras

    Center for Regenerative Medicine, Massachusetts General Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0899-0910
  10. Lai Ping Wong

    Department of Molecular Biology, Massachusetts General Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Ruslan I Sadreyev

    Department of Molecular Biology, Massachusetts General Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. J Tiago Gonçalves

    Dominick Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Amar Sahay

    Center for Regenerative Medicine, Massachusetts, Massachusetts General Hospital, Boston, United States
    For correspondence
    asahay@mgh.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0677-1693

Funding

National Institute of Neurological Disorders and Stroke (R56NS117529)

  • J Tiago Gonçalves

National Institute of Neurological Disorders and Stroke (R56NS117529)

  • Amar Sahay

NA

Reviewing Editor

  1. Joseph G Gleeson, Howard Hughes Medical Institute, The Rockefeller University, United States

Ethics

Animal experimentation: Animals were handled and experiments were conducted in accordance with procedures approved by the Institutional Animal Care and Use Committee (IACUC) at the Massachusetts General Hospital (2011N000084 ) and Albert Einstein College of Medicine in accordance with NIH guidelines.

Version history

  1. Preprint posted: July 14, 2021 (view preprint)
  2. Received: July 14, 2021
  3. Accepted: January 3, 2022
  4. Accepted Manuscript published: January 4, 2022 (version 1)
  5. Version of Record published: February 4, 2022 (version 2)

Copyright

© 2022, Guo et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Nannan Guo
  2. Kelsey D McDermott
  3. Yu-Tzu Shih
  4. Haley Zanga
  5. Debolina Ghosh
  6. Charlotte Herber
  7. William R Meara
  8. James H Coleman
  9. Alexia Zagouras
  10. Lai Ping Wong
  11. Ruslan I Sadreyev
  12. J Tiago Gonçalves
  13. Amar Sahay
(2022)
Transcriptional regulation of neural stem cell expansion in adult hippocampus
eLife 11:e72195.
https://doi.org/10.7554/eLife.72195

Share this article

https://doi.org/10.7554/eLife.72195

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